Notes

Might teacher-perceived parental attention become key point to understand how education relates to later on biological well being? A lifestyle course strategy.
Analysis of translocation breakpoints in human B cell malignancies reveals that DNA double-strand breaks at oncogenes most frequently occur at CpG sites located within 20-600 bp fragile zones and depend on activation-induced deaminase (AID). AID requires single-stranded DNA (ssDNA) to act, but it has been unclear why or how this region transiently acquires a ssDNA state. Here, we demonstrate the ssDNA state in the 23 bp E2A fragile zone using several methods, including native bisulfite DNA structural analysis in live human pre-B cells. AID deamination within the E2A fragile zone does not require but is increased upon transcription. High C-string density, nascent RNA tails, and direct DNA sequence repeats prolong the ssDNA state of the E2A fragile zone and increase AID deamination at overlapping AID hotspots that contain the CpG sites at which breaks occur in patients. These features provide key insights into lymphoid fragile zones generally.Co-translational protein targeting to membranes by the signal recognition particle (SRP) is a universally conserved pathway from bacteria to humans. In mammals, SRP and its receptor (SR) have many additional RNA features and protein components compared to the bacterial system, which were recently shown to play regulatory roles. Due to its complexity, the mammalian SRP targeting process is mechanistically not well understood. In particular, it is not clear how SRP recognizes translating ribosomes with exposed signal sequences and how the GTPase activity of SRP and SR is regulated. Here, we present electron cryo-microscopy structures of SRP and SRP·SR in complex with the translating ribosome. The structures reveal the specific molecular interactions between SRP and the emerging signal sequence and the elements that regulate GTPase activity of SRP·SR. Our results suggest the molecular mechanism of how eukaryote-specific elements regulate the early and late stages of SRP-dependent protein targeting.B lymphocytes are exquisitely sensitive to fluctuations in nutrient signaling by the Rag GTPases, and 15% of follicular lymphomas (FLs) harbor activating mutations in RRAGC. Hence, a potential therapeutic approach against malignant B cells is to inhibit Rag GTPase signaling, but because such inhibitors are still to be developed, efficacy and safety remain unknown. Veliparib cell line We generated knockin mice expressing a hypomorphic variant of RagC (Q119L); RagCQ119L/+ mice are viable and show attenuated nutrient signaling. B lymphocyte activation is cell-intrinsically impaired in RagCQ119L/+ mice, which also show significant suppression of genetically induced lymphomagenesis and autoimmunity. Surprisingly, no overt systemic trade-offs or phenotypic alterations caused by partial suppression of nutrient signaling are seen in other organs, and RagCQ119L/+ mice show normal longevity and normal age-dependent health decline. These results support the efficacy and safety of moderate inhibition of nutrient signaling against pathological B cells.Generation of the primary antibody repertoire requires V(D)J recombination of hundreds of gene segments in the immunoglobulin heavy chain (Igh) locus. The role of interleukin-7 receptor (IL-7R) signaling in Igh recombination has been difficult to partition from its role in B cell survival and proliferation. With a detailed description of the Igh repertoire in murine IL-7Rα-/- bone marrow B cells, we demonstrate that IL-7R signaling profoundly influences VH gene selection during VH-to-DJH recombination. We find skewing toward 3' VH genes during de novo VH-to-DJH recombination more severe than the fetal liver (FL) repertoire and uncover a role for IL-7R signaling in DH-to-JH recombination. Transcriptome and accessibility analyses suggest reduced expression of B lineage transcription factors (TFs) and targets and loss of DH and VH antisense transcription in IL-7Rα-/- B cells. Thus, in addition to its roles in survival and proliferation, IL-7R signaling shapes the Igh repertoire by activating underpinning mechanisms.The hypothesis that reversed, excitatory GABA may be involved in various brain pathologies, including epileptogenesis, is appealing but controversial because of the technical difficulty of probing endogenous GABAergic synaptic function in vivo. We overcome this challenge by non-invasive extracellular recording of neuronal firing responses to optogenetically evoked and spontaneously occurring inhibitory perisomatic GABAergic field potentials, generated by individual parvalbumin interneurons on their target pyramidal cells. Our direct probing of GABAergic transmission suggests a rather anecdotal participation of excitatory GABA in two specific models of epileptogenesis in the mouse CA3 circuit in vivo, even though this does not preclude its expression in other brain areas or pathological conditions. Our approach allows the detection of distinct alterations of inhibition during spontaneous activity in vivo, with high sensitivity. It represents a promising tool for the investigation of excitatory GABA in different pathological conditions that may affect the hippocampal circuit.Although peripheral B cell dysfunction in early HIV infection is established, how B cell subsets are altered by HIV infection is poorly understood. While investigating B cell subsets among individuals recently infected with HIV, we observe an accumulation of CD27-CD38+ B cells and find that these cells can directly facilitate HIV infection of primary CD4+ T cells in vitro. Comprehensive analyses of the phenotype, function, and transcriptome of the CD27-CD38+ B cell subset is conducted compared with memory and naive B cells. We find that the CD27-CD38+ B cells exhibit a transitional B cell phenotype and an extremely high turnover rate. Importantly, individuals with higher proportions of CD27-CD38+ B cells during early HIV infection tend to become rapid progressors in the chronic infection stage. In this study, we identify a peripheral transitional B cell subset that accumulates during early HIV infection and may contribute to disease progression.
Cells of the innate immune system undergo long-term functional reprogramming in response to Bacillus Calmette-Guérin (BCG) exposure via a process called trained immunity, conferring nonspecific protection to unrelated infections. Here, we investigate whether BCG-induced trained immunity is able to protect against infections caused by different Leishmania spp., protozoa that cause cutaneous and mucosal or visceral lesions.

We used training models of human monocytes with BCG and subsequent infection by L. braziliensis, L. amazonensis and L. infantum, and the vaccination of wild-type and transgenic mice for IL-32γ before in vivo challenge with parasites.

We demonstrated that monocytes trained with BCG presented enhanced ability to kill L. braziliensis, L. amazonensis and L. infantum through increased production of reactive oxygen species. Interleukin (IL)-32 appears to play an essential role in the development of trained immunity. Indeed, BCG exposure induced IL-32 production in human primary monocytes, both mRNA and protein.
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